Abstract
The epithelial-to-mesenchymal transition (EMT) is a highly conserved physiological program involved in development and tissue repair; however, its aberrant activation has been implicated in accelerating the progression of a variety of cancers. In breast cancer, the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) are differentially expressed in the clinically more aggressive basal-like subtype compared to luminal subtype of breast cancer and upregulation of miR-221/222 induces the EMT by targeting the 3′ untranslated region (3′UTR) of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1). The complete mechanism through which miR-221/222 promotes the EMT, however, is not fully understood. We identified adiponectin receptor 1 (ADIPOR1), a receptor for the adipocytokine adiponectin, as a direct target of miR-221/222. ADIPOR1 is expressed at higher levels in the luminal compared to the basal-like subtype of breast cancer cell lines, which can be reduced by miR-221/222 targeting of its 3’UTR. In addition, miR-221/222 were negatively correlated with ADIPOR1 expression across breast cancer cell lines and tumors. ADIPOR1 depletion by siRNA in MCF10A cells induced the EMT and increased cell invasion. Depletion of ADIPOR1 by siRNA induced activation of the canonical nuclear factor-kappaB (NF-κB) and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an interleukin 6 (IL6)-dependent manner. Finally, overexpression of ADIPOR1 in the basal-like cell line, MDA-MB-231, attenuated cell invasion and promoted the mesenchymal-to-epithelial transition (MET). We conclude that ADIPOR1 negatively regulates EMT in breast cancer and provides an additional node by which miR-221/222 induces the EMT. These results suggest that ADIPOR1 may play an important role in breast cancer progression and metastasis, and could potentially offer an alternative therapeutic strategy for basal-like breast cancer patients.
Highlights
Breast cancer is a heterogeneous disease, with discrete subtypes that can—in part—be characterized by their pathogenesis, molecular markers, and phenotype [1]
MiR-221 and miR222 expression was negatively correlated with adiponectin receptor 1 (ADIPOR1) mRNA levels across breast cancer cell lines as well as tumors derived from breast cancer patients (Figures 1C – F), suggesting that ADIPOR1 may be an endogenous target of miR-221/222
Small RNA molecules known as miRNAs have emerged as post-transcriptional regulators of mRNA stability, and have been identified to enhance several aspects of breast cancer pathogenesis including metastasis [31], invasion [32], and self-renewal [33]
Summary
Breast cancer is a heterogeneous disease, with discrete subtypes that can—in part—be characterized by their pathogenesis, molecular markers, and phenotype [1]. The basal-like subtype differentially expresses molecular markers such as epithelial cadherin (Ecadherin), vimentin, and fibronectin, commensurate with cells that have undergone EMT. This process gives cells a license to gain mobility and invade through the basement membrane that promotes the intravasation into the vasculature during the early stages of metastasis [8,9]. There currently exists no approved targeted therapies against the triple-negative subtype of breast cancer, but the causal relationship between markers and clinical outcome of basal-like breast cancers suggests the potential for intervention [4,5,6]. As miRNAs have the potential to regulate multiple targets [11], we set out to find additional miR-221/222 targets that could regulate EMT in breast cancer cells
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